Breast cancer susceptibility gene 2 (BRCA2) is a tumor suppressor gene identified on the basis of its genetic linkage to familial breast cancers. Mutations of the BRCA2 gene in humans are associated with predisposition to breast. In fact, BRCA1 and BRCA2 mutations are responsible for the majority of familial breast cancer. Inherited mutations in the BRCA1 and BRCA2 genes account for approximately 7-10% of all breast cancer cases. Women with BRCA mutations have a lifetime risk of breast cancer between 56-87%, and a lifetime risk of ovarian cancer between 27-44%. In addition, mutations in BRCA2 gene have also been linked to various other tumors including, e.g., pancreatic cancer.
A large number of deleterious mutations in BRCA2 gene have been discovered. Genetic testing on patients to determine the presence or absence of such deleterious mutations has proven to be an effective approach in detecting predispositions to breast and ovarian cancers. Genetic testing is now commonly accepted as the most accurate method for diagnosing hereditary breast cancer and ovarian risk.
As deleterious mutations in BRCA2 are associated with predisposition to cancers, particularly breast cancer and ovarian cancer, it is desirable to identify additional naturally existing deleterious mutations in the BRCA2 gene, which may serve as valuable diagnostic markers. However, a large number of genetic variants in BRCA2 gene have been found and the number continues to increase. Many of these variants are misense changes, inframe insertion or deletions, or intron/exon junction changes. Often, it is difficult to understand the effect of such variants, and they are typically reported as “uncertain variants” after genetic testing. There is great need in the art to reclassify such uncertain variants and determine whether they are deleterious mutations or merely clinically insignificant rare polymorphisms.